JCT  Vol.5 No.13 , November 2014
YM155 Inhibits Neuroblastoma Cell Migration and Survival in Vitro and Tumor Growth and Metastatic Burden in a Pre-Clinical Model
Abstract: Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both in vitro and in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15% - 50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25% - 70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma.
Cite this paper: Calderone, H. , Dutta, A. , Smith, L. , Eckardt, A. , Zhao, P. , Sholler, G. (2014) YM155 Inhibits Neuroblastoma Cell Migration and Survival in Vitro and Tumor Growth and Metastatic Burden in a Pre-Clinical Model. Journal of Cancer Therapy, 5, 1289-1302. doi: 10.4236/jct.2014.513129.

[1]   Maris, J.M., Hogarty, M.D., Bagatell, R. and Cohn, S.L. (2007) Neuroblastoma. Lancet, 369, 2106-2120.

[2]   Owens, C. and Irwin, M. (2012) Neuroblastoma: The Impact of Biology and Cooperation Leading to Personalized Treatments. Critical Reviews in Clinical Laboratory Sciences, 49, 85-115.

[3]   American Cancer Society (2012) Cancer Facts and Figures. Atlanta.

[4]   Wagner, L.M. and Danks, M.K. (2009) New Therapeutic Targets for the Treatment of High-Risk Neuroblastoma. Journal of Cellular Biochemistry, 107, 46-57.

[5]   Maris, J.M. (2010) Recent Advances in Neuroblastoma. New England Journal of Medicine, 362, 2202-2211.

[6]   Yoon, K.J. and Danks, M.K. (2009) Cell Adhesion Molecules as Targets for Therapy of Neuroblastoma. Cancer Biology & Therapy, 8, 306-311.

[7]   Ambros, P.F., Ambros, I.M., Brodeur, G.M., Haber, M., Khan, J., Nakagawara, A., Schleiermacher, G., Speleman, F., Spitz, R., London, W.B., et al. (2009) International Consensus for Neuroblastoma Molecular Diagnostics: Report from the International Neuroblastoma Risk Group (INRG) Biology Committee. British Journal of Cancer, 100, 1471-1482.

[8]   Islam, A., Kageyama, H., Takada, N., Kawamoto, T., Takayasu, H., Isogai, E., Ohira, M., Hashizume, K., Kobayashi, H., Kaneko, Y. and Nakagawara, A. (2000) High Expression of Survivin, Mapped to 17q25, Is Significantly Associated with Poor Prognostic Factors and Promotes Cell Survival in Human Neuroblastoma. Oncogene, 19, 617-623.

[9]   Lamers, F., van der Ploeg, I., Schild, L., Ebus, M.E., Koster, J., Hansen, B.R., Koch, T., Versteeg, R., Caron, H.N. and Molenaar, J.J. (2011) Knockdown of Survivin (BIRC5) Causes Apoptosis in Neuroblastoma via Mitotic Catastrophe. Endocrine-Related Cancer, 18, 657-668.

[10]   Yamauchi, T., Nakamura, N., Hiramoto, M., Yuri, M., Yokota, H., Naitou, M., Takeuchi, M., Yamanaka, K., Kita, A., Nakahara, T., et al. (2012) Sepantronium Bromide (YM155) Induces Disruption of the ILF3/p54(nrb) Complex, Which Is Required for Survivin Expression. Biochemical and Biophysical Research Communications, 425, 711-716.

[11]   Cheng, Q., Ling, X., Haller, A., Nakahara, T., Yamanaka, K., Kita, A., Koutoku, H., Takeuchi, M., Brattain, M.G. and Li, F. (2012) Suppression of Survivin Promoter Activity by YM155 Involves Disruption of Sp1-DNA Interaction in the Survivin Core Promoter. International Journal of Biochemistry and Molecular Biology, 3, 179-197.

[12]   Nakahara, T., Kita, A., Yamanaka, K., Mori, M., Amino, N., Takeuchi, M., Tominaga, F., Kinoyama, I., Matsuhisa, A., Kudou, M. and Sasamata, M. (2011) Broad Spectrum and Potent Antitumor Activities of YM155, a Novel SmallMolecule Survivin Suppressant, in a Wide Variety of Human Cancer Cell Lines and Xenograft Models. Cancer Science, 102, 614-621.

[13]   Nakahara, T., Takeuchi, M., Kinoyama, I., Minematsu, T., Shirasuna, K., Matsuhisa, A., Kita, A., Tominaga, F., Yamanaka, K., Kudoh, M. and Sasamata, M. (2007) YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts. Cancer Research, 67, 8014-8021.

[14]   Tang, H.K., Shao, H., Yu, C. and Hou, J.S. (2011) Mcl-1 Downregulation by YM155 Contributes to Its Synergistic Anti-Tumor Activities with ABT-263. Biochemical Pharmacology, 82, 1066-1072.

[15]   Na, Y.S., Yang, S.J., Kim, S.M., Jung, K.A., Moon, J.H., Shin, J.S., Yoon, D.H., Hong, Y.S., Ryu, M.H., Lee, J.L., et al. (2012) YM155 Induces EGFR Suppression in Pancreatic Cancer Cells. PLoS ONE, 7, e38625.

[16]   Feng, W., Yoshida, A. and Ueda, T. (2013) YM155 Induces Caspase-8 Dependent Apoptosis through Downregulation of Survivin and Mcl-1 in Human Leukemia Cells. Biochemical and Biophysical Research Communications, 435, 52-57.

[17]   Lestini, B.J., Goldsmith, K.C., Fluchel, M.N., Liu, X., Chen, N.L., Goyal, B., Pawel, B.R. and Hogarty, M.D. (2009) Mcl1 Downregulation Sensitizes Neuroblastoma to Cytotoxic Chemotherapy and Small Molecule Bcl2-Family Antagonists. Cancer Biology & Therapy, 8, 1587-1595.

[18]   Lamers, F., Schild, L., Koster, J., Versteeg, R., Caron, H.N. and Molenaar, J.J. (2012) Targeted BIRC5 Silencing Using YM155 Causes Cell Death in Neuroblastoma Cells with Low ABCB1 Expression. European Journal of Cancer, 48, 763-771.

[19]   Lladser, A., Sanhueza, C., Kiessling, R. and Quest, A.F. (2011) Is Survivin the Potential Achilles’ Heel of Cancer? Advances in Cancer Research, 111, 1-37.

[20]   Mehrotra, S., Languino, L.R., Raskett, C.M., Mercurio, A.M., Dohi, T. and Altieri, D.C. (2010) IAP Regulation of Metastasis. Cancer Cell, 17, 53-64.

[21]   McKenzie, J.A., Liu, T., Goodson, A.G. and Grossman, D. (2010) Survivin Enhances Motility of Melanoma Cells by Supporting Akt Activation and α5 Integrin Upregulation. Cancer Research, 70, 7927-7937.

[22]   Hingorani, P., Dickman, P., Garcia-Filion, P., White-Collins, A., Kolb, E.A. and Azorsa, D.O. (2013) BIRC5 Expression Is a Poor Prognostic Marker in Ewing Sarcoma. Pediatric Blood & Cancer, 60, 35-40.

[23]   Ghadimi, M.P., Young, E.D., Belousov, R., Zhang, Y., Lopez, G., Lusby, K., Kivlin, C., Demicco, E.G., Creighton, C.J., Lazar, A.J., et al. (2012) Survivin Is a Viable Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors. Clinical Cancer Research, 18, 2545-2557.

[24]   Miller, M.A., Ohashi, K., Zhu, X., McGrady, P., London, W.B., Hogarty, M. and Sandler, A.D. (2006) Survivin mRNA Levels Are Associated with Biology of Disease and Patient Survival in Neuroblastoma: A Report from the Children’s Oncology Group. Journal of Pediatric Hematology/Oncology, 28, 412-417.

[25]   Ito, R., Asami, S., Motohashi, S., Ootsuka, S., Yamaguchi, Y., Chin, M., Shichino, H., Yoshida, Y., Nemoto, N., Mugishima, H. and Suzuki, T. (2005) Significance of Survivin mRNA Expression in Prognosis of Neuroblastoma. Biological and Pharmaceutical Bulletin, 28, 565-568.

[26]   Eslin, D., Lee, C., Sankpal, U.T., Maliakal, P., Sutphin, R.M., Abraham, L. and Basha, R. (2013) Anticancer Activity of Tolfenamic Acid in Medulloblastoma: A Preclinical Study. Tumor Biology, 34, 2781-2789.

[27]   Obexer, P., Hagenbuchner, J., Unterkircher, T., Sachsenmaier, N., Seifarth, C., Bock, G., Porto, V., Geiger, K. and Ausserlechner, M. (2009) Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-Induced Apoptosis. Molecular Biology of the Cell, 20, 2041-2048.

[28]   Hossain, M.M., Banik, N.L. and Ray, S.K. (2012) Survivin Knockdown Increased Anti-Cancer Effects of (?)-Epigallocatechin-3-Gallate in Human Malignant Neuroblastoma SK-N-BE2 and SH-SY5Y Cells. Experimental Cell Research, 318, 1597-1610.

[29]   Mir, R., Stanzani, E., Martinez-Soler, F., Villanueva, A., Vidal, A., Condom, E., Ponce, J., Gil, J., Tortosa, A. and Gimenez-Bonafe, P. (2014) YM155 Sensitizes Ovarian Cancer Cells to Cisplatin Inducing Apoptosis and Tumor Regression. Gynecologic Oncology, 132, 211-220.

[30]   Kaneko, N., Kita, A., Yamanaka, K. and Mori, M. (2013) Combination of YM155, a Survivin Suppressant with a STAT3 Inhibitor: A New Strategy to Treat Diffuse Large B-Cell Lymphoma. Leukemia Research, 37, 1156-1161.

[31]   Kaneko, N., Yamanaka, K., Kita, A., Tabata, K., Akabane, T. and Mori, M. (2013) Synergistic Antitumor Activities of Sepantronium Bromide (YM155), a Survivin Suppressant, in Combination with Microtubule-Targeting Agents in Triple-Negative Breast Cancer Cells. Biological and Pharmaceutical Bulletin, 36, 1921-1927.

[32]   Kita, A., Mitsuoka, K., Kaneko, N., Nakata, M., Yamanaka, K., Jitsuoka, M., Miyoshi, S., Noda, A., Mori, M., Nakahara, T. and Sasamata, M. (2012) Sepantronium Bromide (YM155) Enhances Response of Human B-Cell Non-Hodgkin Lymphoma to Rituximab. Journal of Pharmacology and Experimental Therapeutics, 343, 178-183.

[33]   Liang, H., Zhang, L., Xu, R. and Ju, X.L. (2013) Silencing of Survivin Using YM155 Induces Apoptosis and Chemosensitization in Neuroblastomas Cells. European Review for Medical and Pharmacological Sciences, 17, 2909-2915.

[34]   Iwasa, T., Okamoto, I., Takezawa, K., Yamanaka, K., Nakahara, T., Kita, A., Koutoku, H., Sasamata, M., Hatashita, E., Yamada, Y., et al. (2010) Marked Anti-Tumour Activity of the Combination of YM155, a Novel Survivin Suppressant, and Platinum-Based Drugs. British Journal of Cancer, 103, 36-42.

[35]   Kumar, B., Yadav, A., Lang, J.C., Cipolla, M.J., Schmitt, A.C., Arradaza, N., Teknos, T.N. and Kumar, P. (2012) YM155 Reverses Cisplatin Resistance in Head and Neck Cancer by Decreasing Cytoplasmic Survivin Levels. Molecular Cancer Therapeutics, 11, 1988-1998.

[36]   Yoon, D.H., Shin, J.S., Jin, D.H., Hong, S.W., Jung, K.A., Kim, S.M., Hong, Y.S., Kim, K.P., Lee, J.L., Suh, C., et al. (2012) The Survivin Suppressant YM155 Potentiates Chemosensitivity to Gemcitabine in the Human Pancreatic Cancer Cell Line MiaPaCa-2. Anticancer Research, 32, 1681-1688.

[37]   Chen, J., Pise-Masison, C.A., Shih, J.H., Morris, J.C., Janik, J.E., Conlon, K.C., Keating, A. and Waldmann, T.A. (2013) Markedly Additive Antitumor Activity with the Combination of a Selective Survivin Suppressant YM155 and Alemtuzumab in Adult T-Cell Leukemia. Blood, 121, 2029-2037.

[38]   Kelly, R.J., Thomas, A., Rajan, A., Chun, G., Lopez-Chavez, A., Szabo, E., Spencer, S., Carter, C.A., Guha, U., Khozin, S., Poondru, S., Van Sant, C., Keating, A., Steinberg, S.M., Figg, W. and Giaccone, G. (2013) A Phase I/II Study of Sepantronium Bromide (YM155, Survivin Suppressor) with Paclitaxel and Carboplatin in Patients with Advanced Non-Small-Cell Lung Cancer. Annals of Oncology, 24, 2601-2606.

[39]   Tolcher, A.W., Quinn, D.I., Ferrari, A., Ahmann, F., Giaccone, G., Drake, T., Keating, A. and de Bono, J.S. (2012) A Phase II Study of YM155, a Novel Small-Molecule Suppressor of Survivin, in Castration-Resistant Taxane-Pretreated Prostate Cancer. Annals of Oncology, 23, 968-973.

[40]   Gautier, L., Cope, L., Bolstad, B.M. and Irizarry, R.A. (2004) Affy—Analysis of Affymetrix GeneChip Data at the Probe Level. Bioinformatics, 20, 307-315.

[41]   Samal, K., Zhao, P., Kendzicky, A., Yco, L.P., McClung, H., Gerner, E., Burns, M., Bachmann, A.S. and Sholler, G. (2013) AMXT-1501, a Novel Polyamine Transport Inhibitor, Synergizes with DFMO in Inhibiting Neuroblastoma Cell Proliferation by Targeting both Ornithine Decarboxylase and Polyamine Transport. International Journal of Cancer, 133, 1323-1333.

[42]   Fu, J., Yang, Q.Y., Sai, K., Chen, F.R., Pang, J.C., Ng, H.K., Kwan, A.L. and Chen, Z.P. (2013) TGM2 Inhibition Attenuates ID1 Expression in CD44-High Glioma-Initiating Cells. Neuro-Oncology, 15, 1353-1365.

[43]   Zhang, L., Yeger, H., Das, B., Irwin, M.S. and Baruchel, S. (2007) Tissue Microenvironment Modulates CXCR4 Expression and Tumor Metastasis in Neuroblastoma. Neoplasia, 9, 36-46.

[44]   Crosswell, H.E., Dasgupta, A., Alvarado, C.S., Watt, T., Christensen, J.G., De, P., Durden, D.L. and Findley, H.W. (2009) PHA665752, a Small-Molecule Inhibitor of c-Met, Inhibits Hepatocyte Growth Factor-Stimulated Migration and Proliferation of c-Met-Positive Neuroblastoma Cells. BMC Cancer, 9, 411.

[45]   Yamamura, M., Noguchi, K., Nakano, Y., Segawa, E., Zushi, Y., Takaoka, K., Kishimoto, H., Hashimoto-Tamaoki, T. and Urade, M. (2013) Functional Analysis of Zyxin in Cell Migration and Invasive Potential of Oral Squamous Cell Carcinoma Cells. International Journal of Oncology, 42, 873-880.

[46]   Feng, X., Wu, Z., Wu, Y., Hankey, W., Prior, T.W., Li, L., Ganju, R.K., Shen, R. and Zou, X. (2011) Cdc25A Regulates Matrix Metalloprotease 1 through Foxo1 and Mediates Metastasis of Breast Cancer Cells. Molecular and Cellular Biology, 31, 3457-3471.

[47]   Sikkema, A.H., den Dunnen, W.F., Hulleman, E., van Vuurden, D.G., Garcia-Manero, G., Yang, H., Scherpen, F.J., Kampen, K.R., Hoving, E.W., Kamps, W.A., et al. (2012) EphB2 Activity Plays a Pivotal Role in Pediatric Medulloblastoma Cell Adhesion and Invasion. Neuro-Oncology, 14, 1125-1135.

[48]   Tan Ide, A., Ricciardelli, C. and Russell, D.L. (2013) The Metalloproteinase ADAMTS1: A Comprehensive Review of Its Role in Tumorigenic and Metastatic Pathways. International Journal of Cancer, 133, 2263-2276.

[49]   Malek, A., Catapano, C.V., Czubayko, F. and Aigner, A. (2010) A Sensitive Polymerase Chain Reaction-Based Method for Detection and Quantification of Metastasis in Human Xenograft Mouse Models. Clinical & Experimental Metastasis, 27, 261-271.

[50]   Valentiner, U., Valentiner, F.U. and Schumacher, U. (2008) Expression of CD44 Is Associated with a Metastatic Pattern of Human Neuroblastoma Cells in a SCID Mouse Xenograft Model. Tumor Biology, 29, 152-160.

[51]   Santibanez, J.F., Quintanilla, M. and Bernabeu, C. (2011) TGF-Beta/TGF-Beta Receptor System and Its Role in Physiological and Pathological Conditions. Clinical Science, 121, 233-251.